Fibroblast cell types have been shown to contribute to disease persistence and perpetual damage following injury. Fibroblasts are ubiquitous cells identified by their morphology, production of extracellular matrix and lack of epithelial, vascular and leukocyte lineage markers. They are one of the most abundant cells of the stoma and considered tissue resident cells. While fibroblasts primarily synthesize and remodel the extracellular matrix of tissues, they also have the ability to produce and respond to growth factors allowing paracrine interactions that regulate the morphogenesis of epithelial and endothelial structures in tissues. Thus, fibroblasts play a critical role during tissue development, differentiation and repair in many organs. Presumably, these critical roles for fibroblasts are generally beneficial to a subject, however, deregulation of the molecular mechanisms controlling these critical roles has been found to promote harmful or detrimental affects such as promoting tumor growth, cancer metastases, scar tissue formation, and auto-immunity. For instance, fibroblasts isolated from diseased tissues were shown to be phenotypically different from those taken from normal tissue. Further, fibroblasts have been shown to have a role in cancer at all stages including progression, growth and metastasis. Specifically, at the site of a tumor, the surrounding fibroblasts remain continuously activated, facilitating angiogenesis and cancer progression. In this respect, fibroblasts have great potential as therapeutic targets.
The efficacy of many pharmaceutical agents is predicated on their ability to proceed to the selected target sites and remain there in effective concentrations for sufficient periods of time to accomplish the desired therapeutic or diagnostic purpose. Difficulty in achieving efficacy may be exacerbated by the location and environment of the target site as well as by the inherent physical characteristics of the compound administered. For example, drug delivery via routes subject to repeated drainage or flushing as part of the body's natural physiological functions offer significant impediments to the effective administration of pharmaceutical agents. In this respect, delivery and retention problems are often encountered when administering compounds through the respiratory or gastrointestinal tracts. Repeated administration of fairly large doses is often required to compensate for the amount of drug washed away and to maintain an effective dosing regimen when employing such routes. Such reductions in delivery and retention time complicate dosing regimes, waste pharmaceutical resources and generally reduce the overall efficacy of the administered drug.
In the art, fluorocarbon liquids have been used for treatment of respiratory distress syndrome by removal of lung debris, inflammatory cells and materials by lavage, and by facilitating oxygen delivery. In this capacity, fluorocarbons are used as neat formulations (i.e. liquid formulation with no emulsifying agents). While partial liquid ventilation using perfluorocarbons was shown to improve oxygenation and decrease lung injury in various animal models, clinical trials concluded that neither a high dose nor low dose of perfluorocarbon improved outcome in patients with respiratory distress (See, Kacmarek R M, et al. AM J Respir Crit Care Med. 2006 Apr. 15; 173(8):882-9). Essentially, the perfluorocarbon administered to the patients evaporated before being effective. Larger amounts did not compensate for the evaporation and were not well tolerated by patients.
Accordingly, a need exists for therapeutics and therapeutic delivery vehicles with improved efficacy and target site retention while at the same time minimizing dosage. Also needed is a therapeutic capable of targeting tissue-resident cells and exhibiting anti-fibroblastic activity. The compositions and methods of the present invention provide such anti-fibroblastic therapeutics and therapeutic delivery vehicles with improved efficacy and target site retention while minimizing dosage of toxic agents.